PERK Inhibition Suppresses Neovascularization and Protects Neurons During Ischemia-Induced Retinopathy.
PERK Inhibition Suppresses Neovascularization and Protects Neurons During Ischemia-Induced Retinopathy.
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DOI：
10.1167/iovs.64.11.17
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发表时间：
2023-08-01
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
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作者：
视网膜缺血是多种眼部疾病的常见原因，例如早产儿视网膜病变、糖尿病视网膜病变和静脉阻塞。蛋白激酶RNA激活的类内质网激酶（PERK）是一种主要的内质网应激感受蛋白，与多种疾病有关。在这项研究中，我们研究了PERK在缺血诱导的视网膜病变中的作用，使用小鼠模型氧诱导的视网膜病变（OIR）。通过在出生后第7天（P7）将新生幼仔置于70%氧气中，然后在P12返回室内空气中诱导OIR。将幼仔放回室内空气中后立即经口给予GSK 2606414（一种选择性PERK抑制剂），每日一次，直至样本采集前1天。Western印迹、免疫染色和定量PCR用于评估PERK磷酸化、视网膜变化和与PERK抑制相关的信号传导途径。PERK磷酸化在OIR视网膜中显著增加，其被GSK 2606414抑制。同时，PERK抑制显著减少视网膜新生血管（NV）和视网膜神经节细胞（RGC）损失，恢复星形胶质细胞网络，并促进血管再生。此外，PERK抑制下调单核吞噬细胞的募集/增殖，但不影响OIR上调的经典血管生成途径。我们的研究结果表明，PERK参与缺血诱导的视网膜病变，并且使用GSK 2606414对其进行抑制可以提供有效的治疗干预，旨在减轻视网膜NV，同时防止视网膜缺血期间的神经元损失。
Retinal ischemia is a common cause of a variety of eye diseases, such as retinopathy of prematurity, diabetic retinopathy, and vein occlusion. Protein kinase RNA-activated-like endoplasmic reticulum (ER) kinase (PERK), one of the main ER stress sensor proteins, has been involved in many diseases. In this study, we investigated the role of PERK in ischemia-induced retinopathy using a mouse model of oxygen-induced retinopathy (OIR). OIR was induced by subjecting neonatal pups to 70% oxygen at postnatal day 7 (P7) followed by returning to room air at P12. GSK2606414, a selective PERK inhibitor, was orally administrated to pups right after they were returned to room air once daily until 1 day before sample collection. Western blot, immunostaining, and quantitative PCR were used to assess PERK phosphorylation, retinal changes, and signaling pathways in relation to PERK inhibition. PERK phosphorylation was prominently increased in OIR retinas, which was inhibited by GSK2606414. Concomitantly, PERK inhibition significantly reduced retinal neovascularization (NV) and retinal ganglion cell (RGC) loss, restored astrocyte network, and promoted revascularization. Furthermore, PERK inhibition downregulated the recruitment/proliferation of mononuclear phagocytes but did not affect OIR-upregulated canonical angiogenic pathways. Our results demonstrate that PERK is involved in ischemia-induced retinopathy and its inhibition using GSK2606414 could offer an effective therapeutic intervention aimed at alleviating retinal NV while preventing neuron loss during retinal ischemia.
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影响因子：
13.6
作者：
Liu, Hua;Mei, Fang C.;Cheng, Xiaodong
通讯作者：
Cheng, Xiaodong
影响因子：
17.8
作者：
Gorbatyuk MS;Starr CR;Gorbatyuk OS
通讯作者：
Gorbatyuk OS
影响因子：
4.4
作者：
Gersztenkorn D;Coletta C;Zhu S;Ha Y;Liu H;Tie H;Zhou J;Szabo C;Zhang W;Motamedi M
通讯作者：
Motamedi M
影响因子：
16
作者：
Harding, HP;Zhang, YH;Ron, D
通讯作者：
Ron, D
内质网应激与视网膜炎症和糖尿病性视网膜病有关。
影响因子：
3.5
作者：
Li, Jingming;Wang, Joshua J.;Yu, Qiang;Wang, Min;Zhang, Sarah X.
通讯作者：
Zhang, Sarah X.